Why start antiretroviral therapy for people living with HIV so late?

Photo credit: UCSD.edu

Studies indicate that there are enormous public health benefits of starting antiretroviral therapy (ART) earlier for people living with HIV (PLHIV) then why is ART started so late which severe not only longevity but also considerably reduces quality of life. This was one of the major questions that sparked vibrant academic deliberation at the recently concluded Chennai ART Symposium (CART 2011). CART 2011 was organized in Chennai, India (8-9 January 2011) by Y.R. Gaitonde Centre for AIDS Research and Education (YRG CARE), in collaboration with Centre for AIDS Research (CFAR), Brown University, National Institute of Health (NIH), University of California (San Diego), Karolinska Institute, and HIV Medicine Association of India (HIVMAI).
Although science today suggests starting ART earlier for PLHIV is enormously beneficial and even India’s domestic guidelines recommend starting ART at CD4 below 350 count, the reality is grimmer: we are failing to reach PLHIV early enough with existing AIDS care services. Most PLHIV who show up in ART clinics of YRG CARE have CD4 count below 100, at times as low as 20, 30, or 50 CD4 count, said founder-director of YRG CARE Dr Suniti Solomon, while chairing the inaugural session of CART 2011. Clearly lot more needs to be done to enrol PLHIV in AIDS care services early-on – to improve public health outcomes and their quality of life as well.

The antiretroviral therapy (ART) has undisputed benefits for people living with HIV. "The ART reduces morbidity and mortality from HIV associated opportunistic infections (OI) complications like tuberculosis (TB), reduces morbidity and mortality from co-infections often found in the HIV infected population like hepatitis C (HCV), reduces morbitiy and mortality from the so called non-AIDS events likely related to immune activation, for example cardiovascular diseases (CVD), reduces transmission of HIV to sexual partners and to breastfed infants" said Dr Robert T Schooley, Professor of Medicine, University of California, San Diego, USA, who was one of the prime faculty members at CART 2011.

The current recommendation by the National AIDS Control Organization (NACO), apex agency on HIV/AIDS of Government of India, is to start ART when CD4 count goes below 350. Special recommendations exist in certain cases where ART is started regardless of CD4 count but generally CD4 below 350 or clinically AIDS-associated symptoms are the barometer to assess whether to begin ART or not in NACO’s ART clinics in India.

"Why we are still starting ART in most patients so late? As ART regimens have improved, arguments that patients will run through their drug options if they start earlier are less credible" rightly argued Dr Schooley.

"Initiating ART at lower CD4 counts results in incomplete restoration of CD4 counts, higher risk of AIDS associated malignancy (cancer) and greater risk of virology failure. Among people who started ART at very low CD4 count, the risk of their HIV becoming drug resistant is greater when therapy fails" said Dr Schooley.

"If you are older PLHIV (more than 50 years) the increase in CD4 cell count is not as great as those who are younger (less than 50)" said Dr Schooley.

Narrating the history of ART over the past 30 years, Dr Schooley said that since the time HIV was first diagnosed (1981) to 1986, there were no drugs available. In 1986, a major turning point was that Zidovudine or azidothymidine (AZT) worked. By 1988, the evidence was coming in that AZT works but not for long. By 1996, another milestone was the knowledge that highly active antiretroviral therapy (HAART) works, and for a long time a cure is at hand. By the year 2000, the science indicated that HAART works for a long time but is so toxic that may be it should be used much more sparingly (as per the data from SMART studies). However in 2003, the data showed that stopping HAART in people who were doing well kills them, and causes major morbidity. As we enter the year 2011, we are looking forward to newer and more effective drugs and ways to contain cumulative toxicities.

If starting ART early for PLHIV has such pronounced benefits, then why are we not treating everyone? Probably at the patient level, the challenges like dealing with (at times) severe side-effects, costs, convenience of putting a large population on a therapy that has to be adhered life-long and monitored well, are the barriers. At the structural level, there is surely a funding issue as AIDS money is not adequate and seems unlikely that there will be radical scale up of AIDS money. Also the health systems issue is enormous – with towering needs to strengthen health systems and train healthcare providers in rolling out such an initiative.

However the data is clear: starting ART at very low CD4 count (or very late in HIV progression) has serious adverse outcomes. It significantly ups the risk of non-AIDS morbidities, renal disease (even death due to renal disease), cardiovascular diseases (CVD) among others. Dr Schooley said that in some patients the ART is started so low that it ups their CVD risk comparable to smoking.

On the other hand the risk of opportunistic infections like tuberculosis (TB) and cardiovascular diseases (CVDs) is very low if ART starts at a higher CD4 count.

"Well-powered study could provide definitive answer if it goes to completion" said Dr Schooley. Some ongoing studies like START might finish in 2015.

It is a wise investment of money to start ART early when CD4 count is still high enough – may be 500 count or more. The overall healthcare costs saved if ART is started earlier by not dealing with adverse outcomes that would have come up had ART started late like drug toxicity and other OIs, needs to be considered by policy makers.

If we start ART earlier, harmful effects of uncontrolled viremia at all CD4 levels can be avoided. Also there are more treatment options because of improved potency and tolerability of ART when CD4 count is higher.

The benefits of ART for PLHIV are well established. Current first line ART regimens are less toxic and more convenient than ever before. Limitations are in our ability to pay for and to deliver therapy with currently available resources and decision making about ART must be considered within the context of doing the most good for the most patients for the longest period.